1. Field of the Invention
The present invention relates to a use of Layered Double Hydroxide (LDH) as a drug carrier, and more particularly, to a method of loading a drug onto the LDH drug carrier, a method of improving drug delivery efficiency using the LDH drug carrier, and establishment of a safe dose range of LDH that has no adverse effect in vivo when LDH is administered through injection.
2. Description of the Related Art
Generally, currently available medications have possibility of destroying normal cells as well as diseased cells. Thus, many drugs are limitedly used. There also exist drugs that cannot be used in actual medication due to poor stability in spite of good medicinal activity. In addition, since a single dose is consumed rapidly in the human body during medication, some drugs have inconvenience to be administered several times. In view of these problems of existing drugs, various drug delivery systems capable of assuring good drug delivery efficiency, stability and controlled release rate have been developed.
Basic requirements of drug delivery systems variously depend on desired objectives. Preferentially, drug delivery systems must satisfy the following requirements: 1) drug stability, 2) drug targeting to a specific tissue, 3) regulation of drug release rate and 4) in vivo safety of delivery carriers. Development of organic, inorganic, or polymer drug delivery systems, etc. satisfying these various requirements has been carried out. Internationally developed drug delivery systems are as follows. U.S. Pat. No. 6,361,780, entitled “Microporous Drug Delivery System”, discloses a drug delivery device using porous inorganic oxides, metals, etc. International Patent WO9407468, entitled “Two Phase Matrix for Sustained Release Drug Delivery”, discloses a polymer-silicate phase-based drug delivery system for use as a transdermal patch. U.S. Pat. No. 6,558,703, entitled “Porous Hydroxyapatite Particles as a Carrier for Drug Substances”, discloses a drug delivery system for oral administration which utilizes porous inorganic particles loaded with a sticky/greasy/oily drug substance. U.S. Pat. No. 5,846,952, entitled “Methods and Compositions for Poly-, Beta-, -1-4-N-Acetyl Glucosamine Drug Delivery”, discloses poly-β-1→4-N-acetylglucosamine (p-GlcNAc) polysaccharide as a drug delivery system. In addition, U.S. Pat. No. 5,904,718, entitled “Delayed Drug Delivery System”, discloses a sustained release drug delivery system using inorganic materials. U.S. Pat. No. 5,648,097, entitled “Calcium Mineral-Based Microparticles and Method for the Production thereof”, discloses biodegradable inorganic calcium salt particles used as a drug carrier capable of controlling a drug release rate in the human body. European Patent No. EP1,067,971, entitled “Inorganic Materials for Radioactive Drug Delivery”, discloses an inorganic drug delivery system. Recently, Korean Patent No. 10-0359715, entitled “Bio-inorganic Hybrid Complexes as Gene Reservoir and Potential Delivery Carrier and their Preparation”, and U.S. Pat. No. 6,329,515, entitled “Bio-inorganic Compound Capable of Stable, Solid-State Storage of Genes and Preparation thereof”, disclose that Layered Double Hydroxide (LDH) has the possibility of serving as a reservoir which safely stores DNAs and serving as a gene or drug delivery carrier. In addition, Korean Patent Application No. 2003-00676, entitled “Method of Preventing the Proliferation of Tumor Cells Using MTX-LDH Hybrid”, discloses the prevention of proliferation of osteosarcoma cells using LDH incorporated with MTX which is an anticancer agent.
As described above, research and study on drug delivery systems have been currently actively carried out. In particular, research on drug delivery systems capable of controlling drug stability and release characteristics using polymers or inorganic materials has been most actively carried out. Research on drug delivery systems which increase drug efficacy at a cellular level is also carried out. However, drug delivery systems which is able to be directly used in vivo have not been sufficiently studied. In particular, injectable inorganic drug delivery carriers have been hardly studied.
The present invention is directed to a preparation of a LDH as a drug carrier capable of maximizing in vivo drug delivery efficiency and a use of it in an injectable formulation.
LDH, which is also called “hydrotalcite-like compound”, is a compound having a similar structure to magnesium (Mg)-aluminum (Al) layered double hydroxide known as hydrotalcite, wherein magnesium or aluminum can be substituted by other divalent or trivalent metal. The LDH structure consists of positively charged hydroxide layers due to the presence of trivalent metal ions in substitution of divalent metal ions, and thus various anions can be intercalated between the positively charged hydroxide layers. Thus, a complex obtained by the intercalation of a negatively charged drug between the hydroxide layers of LDH can be used as a drug delivery system. Most of negatively charged drugs can be used herein, which includes various drugs such as methotrexate, vitamins (e.g., vitamin C or retinoic acid), genes with a negatively charged phosphate group, and antisense for gene therapy. It is anticipated that when administered in vivo through injection, LDH containing a negatively charged drug will provide advantages such as drug stability, sustained drug release, and improved drug delivery efficiency, with no harmful side effects along with pharmacological activity.
The present invention relates to the hybridization of nanotechnology and biotechnology. LDH used herein as an injectable drug carrier is an inorganic solid compound and is applied in various fields, including catalysts, supports, thermal stabilizers, antiacids, etc. Depending on the purpose of LDH in these applications, metal composition, particle shape, particle size, etc. must be diversely controlled. Such a control belongs to the category of nanotechnology since it requires microscale or nanoscale particle control and molecular or atomic level modification in composition or physical property. Also for the intercalation of a physiologically active drug molecule into LDH, the interaction between the drug molecule and the LDH is to be controlled. Thus, the present invention also relates to a novel technology which converges medical technology, biotechnology, and nanotechnology. The present invention also relates to biotechnology in the respect that drug efficacy is evaluated after a drug delivery carrier is injected in vivo. Therefore, the present invention is a novel technology that can be accomplished by fusioning nanotechnology and biotechnology.